1. Field of the Invention
The invention relates to the production, purification and use of salts of 6,8-bis(amidiniumthio)octanoic acid, its enantiomers and esters of these compounds. 6,8-bis(amidiniumthio)octanoic acid can be converted by hydrolysis of the isothiuronium grouping to 6,8-dimercaptooctanoic acid (also designated as dihydrolipoic acid), which for its part serves as precursor for the pharmacologically active .alpha.-lipoic acid.
2. Prior Art
The R enantiomer of .alpha.-lipoic acid is a natural substance occurring in practically all animal and vegetable cells. .alpha.-lipoic acid is of essential physiological significance as coenzyme in the oxidative decarboxylation of .alpha.-ketocarboxylic acids (e.g. pyruvic acid). An important pharmacological indication of racemic .alpha.-lipoic acid is diabetic polyneuropathy. In the case of the pure, optical isomers of .alpha.-lipoic acid (R and S form, that is, R .alpha.-lipoic acid and S .alpha.-lipoic acid), in contrast to the racemate the R enantiomer is primarily antiphlogistically and the S enantiomer primarily antinociceptively active (EP 0,427,247, Nov. 8, 1990). Therefore, in addition to the synthesis of racemic .alpha.-lipoic acid the synthesis of the pure enantiomers for purposeful pharmaceutical use is also of great importance.
The previously known synthesis methods utilize various variants for the purposeful introduction of mercapto groups onto derivatives or precursors of octanoic acid which are reported in several passages in the literature. (survey articles: J. S. Yadav et al., J. Sci. Ind. Res. 1990, 49, 400; and A. G. Tolstikov et al., Bioorg. Khim. 1990, 16, 1670; L. Dasaradhi et al., J. Chem. Soc., Chem. Commun. 1990, 729; A. S. Gopalan et al., J. Chem. Perkin Trans. 1 1990, 1897; A. S. Gopalan et al., Tetrahedron Lett. 1989, 5705; EP 0,487,986 A2, Nov. 14, 1991; E. Walton et al., J. Am. Chem. Soc. 1955, 77, 1955; D. S. Acker and W. J. Wayne, J. Am. Chem. Soc. 1957, 79, 6483; L. G. Chebotareva and A. M. Yurkevich, Khim.-Farm. Zh. 1980, 14, 92).
Problematic areas in all production variants described are on the one hand multistage synthesis sequences with at times low reaction yields which do not permit an economic operation, or the instability of intermediate stages, which prevents their industrial purification. The required purity for pharmaceutical items can therefore only be achieved by expensive final purification by distillation of the dihydrolipoic acid (6,8-dimercaptooctanoic acid) II and/or by multiple crystallization of the sensitive .alpha.-lipoic acid I, which results in considerable product losses. For example, GB 996,703 can be cited with its conversion of 6-hydroxy-.DELTA.7-octanoic acid or its esters in which yields of 23 to 51% of theory of dimercaptooctanoic acid II and .alpha.-lipoic acid I were obtained by distillation. ##STR1##